CN112521393A - Preparation method of methyl pheophorbide a - Google Patents
Preparation method of methyl pheophorbide a Download PDFInfo
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- CN112521393A CN112521393A CN201910879793.1A CN201910879793A CN112521393A CN 112521393 A CN112521393 A CN 112521393A CN 201910879793 A CN201910879793 A CN 201910879793A CN 112521393 A CN112521393 A CN 112521393A
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings
Abstract
The invention belongs to the field of pharmacy, and relates to a preparation method of methyl pheophorbide a. The preparation method comprises the steps of taking a substance containing chlorophyll a as a starting material, extracting the chlorophyll a by using an organic solvent to obtain chlorophyll a, performing magnesium removal and methyl esterification on the chlorophyll a to obtain a methyl pheophorbide a product, and optionally further purifying the product to finally obtain a high-purity refined product of the methyl pheophorbide a. Compared with the prior literature method, the method has the obvious advantages of high process yield and high product purity, reduces the treatment process of waste acid, reduces the environmental pollution and saves the production cost.
Description
Technical Field
The invention belongs to the field of pharmacy, and particularly relates to a preparation method of methyl pheophorbide a.
Background
Photodynamic therapy is another new tumor treatment technology after surgery, radiotherapy and chemotherapy. The treatment is based on irradiating tumor tissues enriched with photosensitizer by light with a certain wavelength, and inducing effects such as photodynamic and the like by the photosensitizer, so that the tumor tissues are necrotized to show a treatment effect. Research shows that the chlorin e6 has reliable photodynamic curative effect on mouse solid sarcoma-180 transplantation tumor, and compared with the photosensitizer clinically used at home and abroad, the photosensitizer has the characteristics of definite chemical structure, higher absorption coefficient of a red light treatment area by one order of magnitude than that of a porphyrin preparation, strong photosensitization, high clearance speed in vivo, low toxicity and the like.
Pheophorbide a methyl ester is a key intermediate for the preparation of chlorin e 6. The methyl pheophorbide a reported in the literature at present is directly prepared from spirulina powder serving as a starting material in a mixed solution of methanol and concentrated sulfuric acid. The product obtained by the method contains more impurities, and part of the impurities are difficult to remove through column chromatography. The experimental comparison shows that the yield of the direct preparation of the methyl pheophorbide a from the spirulina powder is lower, and the total mass yield is 0.05-0.10%. Therefore, the method for preparing the methyl pheophorbide a has poor product purity and higher cost.
Summary of The Invention
The invention aims to provide a method for preparing methyl pheophorbide a by extracting chlorophyll a from a chlorophyll a-containing substance. The invention also provides a method for effectively refining methyl pheophorbide a.
In order to achieve the purpose, the technical scheme of the invention is as follows: extracting chlorophyll a-containing substances by an organic solvent to obtain chlorophyll a, and preparing a methyl pheophorbide a product from the chlorophyll a through demagging and methyl esterification reactions. According to the requirement, the technical scheme also optionally comprises the steps of further purifying the methyl pheophorbide a product, and obtaining a high-purity refined product (the purity is more than 99%) of the methyl pheophorbide a through pulping and recrystallization.
The improvement of the invention is that the preparation process comprises the steps of extracting chlorophyll a from a substance containing chlorophyll a, removing more impurities, and then preparing the methyl pheophorbide a product from the chlorophyll a through the reactions of magnesium removal and methyl esterification. The product of methyl pheophorbide a has high purity and less impurities difficult to remove.
The method takes a substance containing chlorophyll a as a starting material, and obtains a methyl pheophorbide a product by sequentially carrying out extraction, demagging and methyl esterification, wherein the process route is as follows:
the preparation process comprises the following specific operation steps:
(1) extraction of
Adding chlorophyll a-containing material (such as Spirulina powder) into the extraction solvent, and stirring under heating and refluxing conditions in dark for 2 hr. Cooling the reaction system, filtering, and storing the filtrate in dark. The cake was further extracted 2 times as described above. And (4) decompressing and evaporating the filtrate extracted for 3 times to obtain chlorophyll a.
(2) Demagging, methyl esterification
And (2) adding the chlorophyll a obtained in the step (1) into anhydrous methanol, and dropwise adding concentrated sulfuric acid. After dropping, the mixture was stirred at room temperature in the dark until HPLC monitoring no further increase in methyl pheophorbide a. Purified water was added to the reaction solution, and the pH was adjusted to 5 to 6 with a 10% NaOH solution. After removing methanol from the reaction system under reduced pressure, the remaining solution was filtered through a celite pad. After filtration to dryness, the diatomaceous earth was eluted with purified water, n-heptane and a mixed solvent of acetone and dichloromethane, respectively. The solution of acetone and dichloromethane was collected and evaporated to dryness under reduced pressure. Adding a small amount of anhydrous methanol into the reaction bottle, uniformly stirring, filtering, and drying a filter cake to obtain a methyl pheophorbide a product.
Another improvement of the present invention is that the refining process is optional and comprises further purifying the above-described methyl pheophorbide a product by pulping and recrystallization to obtain a refined product of methyl pheophorbide a having a purity of more than 99% (e.g., more than 99.0%, 99.1%, 99.2%, 99.3%, 99.4%, or even more than 99.5%).
The refining process comprises the following specific operation steps:
and (3) adding the methyl pheophorbide a product obtained in the step (2) into a pulping solvent, stirring and pulping at room temperature for 1h, filtering, and drying a filter cake in vacuum. Adding the dried methyl pheophorbide a into a recrystallization solvent, heating to reflux, and after all the methyl pheophorbide a is dissolved, closing the heating and slowly cooling for crystallization. Cooling to room temperature, stirring and crystallizing for 2 h. Filtering, leaching the filter cake with a recrystallization solvent, and drying to obtain a high-purity refined product of the methyl pheophorbide a.
Specifically, the invention provides a preparation method of methyl pheophorbide a, which comprises the following steps:
1) using chlorophyll a-containing substance as starting material, extracting with organic solvent to obtain chlorophyll a, and
2) and the methyl pheophorbide a is obtained by the demagging and methyl esterification of the chlorophyll a.
Preferably, the preparation method of the invention further comprises the following refining steps:
3) further purifying to obtain high-purity refined product of methyl pheophorbide a.
According to the invention, the extraction step 1) described above is carried out protected from light and from an inert gas, preferably argon and nitrogen.
According to the present invention, the chlorophyll-a containing substance includes, but is not limited to, Spirulina powder (e.g., Spirulina platensis powder, or Spirulina maxima (Spirulina maxima) powder), silkworm excrement, chlorella powder, dried nettle leaf powder, freeze-dried spinach leaf, and the like.
According to the present invention, the organic solvent for extracting chlorophyll a is not limited as long as it dissolves chlorophyll a, and includes alkanes such as n-hexane, n-heptane, toluene, cyclohexane, ethers such as tetrahydrofuran, dioxane, diethyl ether, nitriles such as acetonitrile, propionitrile, alcohols such as methanol, ethanol, isopropanol, ketones such as acetone, butanone, esters such as ethyl acetate, isopropyl acetate, butyl acetate, or mixtures of the above solvents, preferably acetone, butanone, methanol, ethanol or mixtures thereof. The amount of the organic solvent used is 2 to 8 times (v/mass), preferably 4 to 6 times (v/mass) the amount of the starting material.
According to the present invention, the pheophytin a is demagging and methyl esterification in a mixed solution of methanol and concentrated sulfuric acid. The amount of methanol is 1 to 15 times (volume/mass), preferably 5 to 8 times (volume/mass) that of chlorophyllin a; the amount of concentrated sulfuric acid used is 0.1 to 1.0 times (volume/mass), preferably 0.3 to 0.5 times (volume/mass) of chlorophyllin a.
According to the present invention, the refining step of methyl pheophorbide a comprises the steps of firstly pulping methyl pheophorbide a with a pulping solvent to carry out primary refining, drying the pulping sample, and then carrying out recrystallization refining with an organic solvent to obtain a refined product of methyl pheophorbide a. Wherein the pulping solvent comprises alcohols (such as methanol, ethanol, isopropanol); alkanes (e.g., n-hexane, n-heptane, cyclohexane); ketones (e.g., acetone, butanone); esters (e.g., ethyl acetate, isopropyl acetate, butyl acetate); halogenated hydrocarbons (e.g., dichloromethane, chloroform); ethers (e.g., tetrahydrofuran, dioxane, diethyl ether); water, or a mixture of two or more of the above solvents, preferably methanol, n-hexane, acetone, dichloromethane, ethyl acetate or a mixture thereof. Recrystallization solvents include ketones (e.g., acetone, butanone, pentanone); esters (e.g., ethyl acetate, isopropyl acetate, butyl acetate); halogenated hydrocarbons (e.g., dichloromethane, chloroform); ethers (e.g. tetrahydrofuran, dioxane, diethyl ether), or mixtures thereof, preferably acetone, ethyl acetate, dichloromethane or mixtures thereof.
According to the present invention, the beating solvent is used in an amount of 5 to 20 times (v/mass), preferably 10 to 12 times (v/mass) as much as methyl pheophorbide a, and the recrystallization solvent is used in an amount of 10 to 70 times (v/mass), preferably 30 to 50 times (v/mass) as much as methyl pheophorbide a.
Aiming at the low-purity crude methyl pheophorbide a obtained by the prior art or other preparation methods, the invention also provides a method for preparing a refined product of methyl pheophorbide a by purifying the crude product of methyl pheophorbide a, which comprises the following steps: firstly, pulping the crude product of the pheophorbide alpha methyl ester by using a pulping solvent for primary refining, drying a pulping sample, and then recrystallizing by using an organic solvent to obtain a refined product of the pheophorbide alpha methyl ester. Wherein the dosage of the pulping solvent and the recrystallization solvent is the same as that of the refined methyl pheophorbide a product.
The invention improves the defects of poor purity, low yield and need of column chromatography purification of the product obtained by the existing preparation method of methyl pheophorbide a. The chlorophyll a-containing substance is extracted and treated to obtain the chlorophyll a, more impurities which can generate side reaction in subsequent demagging and methyl esterification are removed, and the prepared methyl pheophorbide a has higher purity and less impurity content which is difficult to remove. After a large amount of experimental data, the inventor surprisingly finds that the recrystallization solvent has a good effect of removing impurities in methyl pheophorbide a, and the methyl pheophorbide a with the purity of more than 99% can be prepared under the condition of high yield.
Drawings
FIG. 1 shows the results of purity measurements of crude methyl pheophorbide a prepared directly from spirulina powder according to the comparative example method;
FIG. 2 is a result of examining the purity of a purified product of methyl pheophorbide a prepared from a crude product of methyl pheophorbide a according to a comparative example method;
FIG. 3 shows the results of examining the purity of a methyl pheophorbide a product prepared according to the method of the present invention; and
FIG. 4 shows the results of examining the purity of a purified product of high-purity methyl pheophorbide a prepared from a methyl pheophorbide a according to the method of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the technical solutions of the present invention will be described in detail and fully below with reference to specific embodiments of the present invention. It is to be understood that the embodiments described are only a few embodiments of the present invention, and not all embodiments. All variations that can be obtained by a person skilled in the art without making creative efforts based on the embodiments of the present invention belong to the claimed scope of the present invention.
The reagents and starting materials used in the present invention are commercially available.
Example 1: extraction of chlorophyll-a
5L of acetone is added into a 10L reaction bottle, and 1Kg of spirulina powder is added under the condition of mechanical stirring. Continuously introducing argon into the system, and extracting chlorophyll a under the condition of light-proof reflux. After 2h, the heating was stopped, the mixture was cooled and filtered, and the solvent was removed from the filtrate under reduced pressure. Returning the filter cake to the reaction bottle, and continuously adding 5L of acetone for reflux extraction. Extracting for three times continuously, combining the filtrates, and evaporating to dryness to obtain 50g chlorophyll a with mass yield of 5.00%.
Example 2: preparation of methyl pheophorbide a
300mL of anhydrous methanol was added to 50g of chlorophyll a of example 1, and after stirring the mixture uniformly, the mixture was transferred to a 1L reaction flask and stirred in an ice-water bath in the dark. 15mL of concentrated sulfuric acid is dripped into the reaction bottle, and the temperature is controlled not to exceed 30 ℃ in the dripping process. After dropping, the reaction flask was kept in the dark and stirred at room temperature until the content of methyl pheophorbide a in the reaction solution did not increase.
After the reaction was completed, the reaction solution was filtered, and the filter cake was washed with 50mL of anhydrous methanol. The filtrate was adjusted to pH 6 with 10% NaOH solution. After removing methanol from the reaction solution under reduced pressure, the reaction solution was filtered through celite, and then the celite was washed with purified water until the filtrate was pale yellow or brown. And continuously pumping the filter cake, adding 50ml of n-hexane, soaking the diatomite for 20min, pumping, and repeatedly washing for 1 time. Then soaking the diatomite in 100mL of acetone for 20min, and then pumping to dry; the diatomaceous earth was soaked with 100mL of a mixture (1:1) of acetone and dichloromethane for 20min and then drained. The filtrate and the acetone solution from the previous step were combined and the solvent was removed under reduced pressure. Adding 25mL of anhydrous methanol into a reaction bottle, stirring at room temperature for 20min, filtering, and drying to obtain 6.10g of methyl pheophorbide a product, wherein the yield is 12.20%, and the purity is 95.35%.
Example 3: refining of methyl pheophorbide a
6.00g of the methyl pheophorbide a product obtained in example 2 was added to 60mL of anhydrous methanol, slurried at room temperature for 1 hour, filtered, and the filter cake was added to 240mL of acetone and refluxed for 0.5 hour while being stirred away from light. And closing heating and naturally cooling for crystallization. Cooling to room temperature, stirring for crystallization for 2h, filtering, leaching the filter cake with 10ml acetone, and drying to obtain 2.40g of high-purity refined product of methyl pheophorbide a with yield of 40% and purity of 99.24%.
Example 4 (comparative example)
According to the literature method for preparing methyl pheophorbide a in general (CN1512994A), crude methyl pheophorbide a is directly prepared from spirulina powder.
5L of anhydrous methanol was added to the reaction flask, and 1Kg of spirulina powder was added under stirring. After stirring uniformly, 500mL of concentrated sulfuric acid is added dropwise, and stirring is carried out for 3h at room temperature after the addition is finished. Diluting with cold water, filtering with diatomite, washing with water, ethanol and hexane, and removing methyl pheophorbide a with acetone. The acetone solution is concentrated and recrystallized to obtain 2.50g of crude methyl pheophorbide a with the mass yield of 0.25 percent and the purity of 82.22 percent.
According to the method of example 3, the crude product was purified once to obtain 0.88g of a purified methyl pheophorbide a having a purity of 94.35% and a yield of 35.20%.
Examples 1 to 3 above are processes for producing methyl pheophorbide a according to the present invention, and example 4 is a process for producing methyl pheophorbide a disclosed in the general literature. For a better comparison of the invention, the purity and yield of the products obtained from the two preparation methods are compared, as shown in table 1 below and in figures 1 to 4:
TABLE 1 summary of yields and purities of the two methods
The purity and yield of the methyl pheophorbide a prepared by the method are obviously higher than those of the products prepared by the methods in the general literature. The analysis reason is that the pheophorbide alpha methyl ester prepared by the method has less impurities with retention time of about 4.80min under the existing HPLC condition, and the impurities are the impurities which are difficult to remove in the pheophorbide alpha methyl ester, so that the product quality is influenced. The HPLC test results of the samples are shown in the following Table 2:
TABLE 2 summary of major impurities for samples prepared by two methods
Therefore, compared with the prior literature method, the preparation method of the methyl pheophorbide a has the obvious advantages of high process yield and high product purity. Meanwhile, the solvent used in the method can be recycled and reused, the consumption of concentrated sulfuric acid in the process of preparing the methyl pheophorbide a is obviously reduced, the treatment process of waste acid is reduced, the environmental pollution is reduced, and the production cost is saved.
Claims (11)
1. A preparation method of methyl pheophorbide a comprises the following steps:
1) using chlorophyll a-containing substance as starting material, extracting with organic solvent to obtain chlorophyll a, and
2) and the methyl pheophorbide a is prepared by the pheophorbide a through demagging and methyl esterification.
2. The method of claim 1, further comprising the following refining steps:
3) the methyl pheophorbide a is further purified to obtain a purified product of high purity (preferably 99% or more).
3. The method of claim 1 or 2, wherein the chlorophyll-a-containing substance is selected from the group consisting of spirulina powder (e.g., spirulina platensis powder or spirulina maxima powder), silkworm excrement, chlorella powder, dried nettle leaf powder and freeze-dried spinach leaf.
4. A process according to any one of claims 1 to 3, characterized in that the organic solvent for extracting chlorophyll-a is selected from alkanes (e.g. n-hexane, n-heptane, toluene, cyclohexane), ethers (e.g. tetrahydrofuran, dioxane, diethyl ether), nitriles (e.g. acetonitrile, propionitrile), alcohols (e.g. methanol, ethanol, isopropanol), ketones (e.g. acetone, butanone), esters (e.g. ethyl acetate, isopropyl acetate, butyl acetate), or mixtures of the above solvents, preferably acetone, butanone, methanol, ethanol or mixtures thereof.
5. The process according to any one of claims 1 to 4, wherein the organic solvent is used in an amount of 2 to 8 times (v/mass), preferably 4 to 6 times (v/mass) the amount of the starting material.
6. The method according to claim 1, wherein the pheophytin a is subjected to demagging and methyl esterification in a mixed solution of methanol and concentrated sulfuric acid.
7. The process according to claim 6, wherein methanol is used in an amount of 1 to 15 times (v/mass), preferably 5 to 8 times (v/mass) the amount of chlorophyll a, and concentrated sulfuric acid is used in an amount of 0.1 to 1.0 times (v/mass), preferably 0.3 to 0.5 times (v/mass) the amount of chlorophyll a.
8. The process according to claim 2, wherein the refining step comprises the steps of preliminarily refining the methyl pheophorbide a by beating with a beating solvent, drying the beaten sample, and then refining by recrystallization with an organic solvent,
wherein the pulping solvent is selected from alcohols (such as methanol, ethanol, isopropanol); alkanes (e.g., n-hexane, n-heptane, cyclohexane); ketones (e.g., acetone, butanone); esters (e.g., ethyl acetate, isopropyl acetate, butyl acetate); halogenated hydrocarbons (e.g., dichloromethane, chloroform); ethers (e.g., tetrahydrofuran, dioxane, diethyl ether); water, or a mixture of two or more of the above solvents, preferably methanol, n-hexane, acetone, dichloromethane, ethyl acetate or mixtures thereof,
the recrystallization solvent is selected from ketones (e.g., acetone, butanone, pentanone); esters (e.g., ethyl acetate, isopropyl acetate, butyl acetate); halogenated hydrocarbons (e.g., dichloromethane, chloroform); ethers (e.g. tetrahydrofuran, dioxane, diethyl ether), or mixtures thereof, preferably acetone, ethyl acetate, dichloromethane or mixtures thereof.
9. The production process according to claim 8, wherein the beating solvent is used in an amount of 5 to 20 times (v/mass), preferably 10 to 12 times (v/mass) as much as a methyl pheophorbide a, and the recrystallization solvent is used in an amount of 10 to 70 times (v/mass), preferably 30 to 50 times (v/mass) as much as a methyl pheophorbide a.
10. A method for preparing a refined product of methyl pheophorbide a by purifying a crude product of methyl pheophorbide a, comprising the following refining steps:
firstly, pulping the crude product of the methyl pheophorbide a by using a pulping solvent for primary refining, and,
drying the pulped sample, recrystallizing with organic solvent to obtain refined product of methyl pheophorbide a,
wherein the pulping solvent is selected from alcohols (such as methanol, ethanol, isopropanol); alkanes (e.g., n-hexane, n-heptane, cyclohexane); ketones (e.g., acetone, butanone); esters (e.g., ethyl acetate, isopropyl acetate, butyl acetate); halogenated hydrocarbons (e.g., dichloromethane, chloroform); ethers (e.g., tetrahydrofuran, dioxane, diethyl ether); water, or a mixture of two or more of the above solvents, preferably methanol, n-hexane, acetone, dichloromethane, ethyl acetate or mixtures thereof,
the recrystallization solvent is selected from ketones (e.g., acetone, butanone, pentanone); esters (e.g., ethyl acetate, isopropyl acetate, butyl acetate); halogenated hydrocarbons (e.g., dichloromethane, chloroform); ethers (e.g. tetrahydrofuran, dioxane, diethyl ether), or mixtures thereof, preferably acetone, ethyl acetate, dichloromethane or mixtures thereof.
11. The process according to claim 10, wherein the beating solvent is used in an amount of 5 to 20 times (v/mass), preferably 10 to 12 times (v/mass) as much as the crude methyl pheophorbide a, and the recrystallization solvent is used in an amount of 10 to 70 times (v/mass), preferably 30 to 50 times (v/mass) as much as the crude methyl pheophorbide a.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116162092A (en) * | 2023-03-03 | 2023-05-26 | 康俄(上海)医疗科技有限公司 | Preparation method of chlorin e6 triglucamine salt |
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| CN101531663A (en) * | 2008-03-13 | 2009-09-16 | 北京科莱博医药开发有限责任公司 | Method for preparing methyl pheophorbide-A from water-blooming cyanobacteria |
| CN103031354A (en) * | 2012-12-29 | 2013-04-10 | 西安岳达植物科技有限公司 | Method for extracting pheophorbide A from spirulina |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN116162092A (en) * | 2023-03-03 | 2023-05-26 | 康俄(上海)医疗科技有限公司 | Preparation method of chlorin e6 triglucamine salt |
| CN116162092B (en) * | 2023-03-03 | 2023-10-10 | 康俄(上海)医疗科技有限公司 | Preparation method of chlorin e6 triglucamine salt |
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